The objectives of this program comprise a coordinated approach to the design, synthesis and pharmacological evaluation of chemotherapeutic agents with specific emphasis on the development of safe and effective agents for the mass treatment of infections with Schistosoma mansoni and Schistosoma japonicum. A number of nitroheterocyclic and nitroaromatic compounds possess a broad spectrum of antiparasitic and antibiotic activities. Some have uniquely desirable attributes for the chemotherapy of schistosomiasis. Optimum formulations, dose schedules and mechanisms of action of these agents will continue to be studied. Some of these compounds are capable of eliciting in various systems undesirable toxicities such as mutagenicity, teratogenicity and carcinogenesis. Dissociation of these toxicities from chemotherapeutic action has been achieved by structural modification of the parent compound or by suppression of the formation of mutagenic metabolites. Studies on structure-activity relations, mode of action, and metabolism of these agents will form the basis for continuing efforts to dissociate toxic from chemotherapeutic activity. Manipulation of the metabolic machinery responsible for drug metabolism offers further possibilities in this regard. Elucidation of the physiological roles of neurotransmitters in schistosomes and their molluscan hosts may reveal potential targets for chemotherapy. Since a large proportion of the energy of adult schistosomes is derived from glycolysis (the target of trivalent organic antimonials) we are exploring the possibility of achieving multiple blockade of the glycolytic pathway as a means for achieving synergistic chemotherapeutic effects. Snails of the species Biomphalaria glabrata refractory to schistosomal infections will be studied in an effort to uncover the mechanism of this genetically determined state. Such snails could offer a mechanism for the biological control of the transmission of schistosomiasis, through the principle of competitive displacement.